Are all AR inhibitors the same?

[yeatz]

Hi, I'm back! Got a question about AR inhibitors,

specifically darolutamide (Nubeqa) & enzalutamide (Xtandi).

Been fighting PC for seven years; Gleason 8; radiation, then

recurrence. Has metastasized to lymph nodes, but not bones.

Took Abiraterone (Zytiga); didn't work. Took docetaxel (Taxotere);

worked for several months. Just finished 3 cycles of darolutamide

(Nubeqa); PSA shot up from 33.6 to 50. MO now prescribes

cabazitaxel (Jevtana).

My question: Why not try enzalutamide first? MO says all

AR inhibitors are the same: "They change one molecule and

sell it as a new drug." But when daro was approved, all the

medical mags said it was "structurally unique" and "structurally

distinct" from other ARI's (partly because it had two

pharmacologically active diastereomers, which is beyond

me!) So: If one didn't work, why not at least try the other?

Part of this is my concern about cabaz & its side effects, which

I've read about in detail here. But also want to make sure

we're not missing an opportunity.

Do you think that if one AR inhibitor fails, all others will too?

Many thanks,

yeatz

[Tall_Allen]

There is a lot of cross-resistance in all these medicines targeted at the androgen receptor (AR). Darolutamide is not approved for metastatic CRPC, although it probably works as well as any of the other second generation anti-androgens. Apalutamide and darolutamide are supposed to prevent AR upgrading. There have been no comparative tests yet.

[yeatz in reply to Tall_Allen]

Thanks for your reply. I should note that darolutamide is approved for lymph node metastasis, as long as it's local or regional. (In their Phase III study for FDA, theysimply didn't include lymph nodes; made it sound like they weren't doing mets of

any kind. But FDA did approve daro for lymph node mets.)

When you say cross-resistance, what exactly do you mean? If one fails, does that

mean the others will, too?

[Tall_Allen in reply to yeatz]

Yes, you are right that Nubeqa is approved for any non-M1 CRPC. Yes, cross resistance means that once the cancer is resistant to one, the others will not work for very long.

[tango65]

You could discuss having a direct biopsy if possible or a liquid biopsy to study the genome of the cancer and do immunohistochemistry analysis (IHC) to see if there are specific mutations and / or markers which could make the cancer susceptible to treatments with drugs such as olaparib, rucaparib, keytruda or chemo with platinum compounds (cisplatin, carboplatin etc.).

[yeatz in reply to tango65]

Good advice. I had PC samples sent to genome analysts several months ago; unfortunately, no matches. But it's

good advice; everybody should do it. I've read that genome

people can now identify gene mutation in about 25 per cent

of PC samples.

[tango65 in reply to yeatz]

I wish you the best of luck on your journey.!

[ResidentPhysician]

Any reason Why haven’t you tried anti parasitics?

[yeatz in reply to ResidentPhysician]

Because I don't know what they are! Can you explain?

[LearnAll]

In broader sense, Anti Androgens have similarities ...They all block DHT/T from activating Androgen Receptor and thus, deprive the cancer cells of essential substance they need to divide and grow.However, there are many differences...when it comes to side effects. e.g. Bicalutamide causes least heart related side effects whereas Abiraterone causes most cardiac side effects.

Studies have shown that risk of major cardiac side effects are 1% in placebo group, 2% in Bicalutamide group, 6% in Enzalutamide group and 14% in Abiraterone group.

And Enzalutamide causes seizures in some men. Darolutamide and Apalutamide are too new to really know about their side effects.

As for cross resistance....Not a 100% phenomenon. There are cases where men who failed Bicalutamide but then responded to first generation meds like Flutamide.

One of the main mechanism of resistance is androgen receptor amplification..meaning that now a stronger Anti Androgen is needed to have same effect...so once Bicalutamide fails..it makes sense to upgrade to Enzalutamide as the later is stronger AR blocker albeit with more side effects.

[kaptank in reply to LearnAll]

Bicalutamide generally does not have cross resistance and closes no options. Abi and enza have a degree of cross resistance (take abi before enza to lessen it).The newer lutamides are too new to tell.

[yeatz in reply to LearnAll]

Thank you. That sounds logical. I'm long past bicalutamide; have just stopped darolutamide, which didn't work. I gather

that main problem is this: when any AR inhibitor is tried,

the PC cells manufacture more ARs than inhibitor can disable.

So starting a new one would, if anything, just cause the PC

to make more receptors. Is that an accurate summation?

[LearnAll in reply to yeatz]

Yes. That is what is called AR Amplification...Result is that now a small amount of DHT/T is enough to make cancer cells grow.

[yeatz in reply to LearnAll]

Many thanks! You've resolved my question, and increased my knowledge!